12:00 AM
 | 
Jul 25, 2016
 |  BioCentury  |  Strategy

Paving the way

How Amgen, Sandoz IP battles may unleash a flood of Humira, Enbrel biosimilars

Amgen Inc. and the Sandoz unit of Novartis AG are charting a course that could create competitive U.S. markets for two of the biggest prizes in the biosimilars universe, AbbVie Inc.'s Humira adalimumab and Amgen's Enbrel etanercept, which together had U.S. sales of $13.4 billion in 2015.

Unanimous advisory committee endorsements for ABP 501, Amgen's version of adalimumab, and GP2015, Sandoz's etanercept, suggest the two companies have overcome the formidable scientific and regulatory hurdles to gaining the first FDA approvals for self-injectable biosimilars.

The two companies adopted regulatory strategies that went beyond FDA's minimum requirements.

To increase the chances of FDA approval and bolster the confidence of physicians and patients, Amgen gold-plated its development program by conducting a clinical trial that the agency said was unnecessary.

Sandoz, with one eye on a future application for interchangeability and the other looking to persuade physicians to switch patients from branded Enbrel to biosimilar GP2015, incorporated a switching extension in its clinical trial that the agency had not asked for and excluded from its review.

Once they have FDA approval, Amgen and Sandoz will have to bash holes through dense patent thickets, and create and execute commercial and marketing strategies suited to the new competitive landscape.

AbbVie has over 70 Humira patents that it claims will keep biosimilars off the U.S. market until 2022.

Amgen has stated that it could launch its biosimilar Humira "as soon as 2017," but the best-case scenario for launching with minimal IP risk is late 2018 or early 2019.

Sandoz hasn't provided guidance on the launch date for its etanercept, but it must win pending litigation or wait for the expiration of Amgen's Enbrel patents in 2029.

The commercial environment will be complex because AbbVie and Amgen have additional defenses against erosion of the Humira and Enbrel markets, including exploiting physician and patient skepticism about biosimilars, using discounts and rebates to undercut biosimilar pricing and adding new indications.

Marketing and support will be critically important because the products are chronically self-administered, unlike biosimilars of oncology products.

After having overcome all of these challenges, there is also a real risk the biosimilar pioneers could find themselves in a crowded, chaotic marketplace.

Amgen's and Sandoz's success in punching holes in the Humira and Enbrel IP defenses will lower the barriers to market for competitors that are poised to swarm onto the market. At that point, a Darwinian selection based on marketing prowess and manufacturing capacity and costs could determine which biosimilar Humiras and Enbrels survive and thrive (see "Humira Biosimilars" & "Enbrel Biosimilars," page 3).

Over-studying

FDA staff usually adopt a neutral or even adversarial stance toward drug sponsors at advisory panels. But at the Arthritis Advisory Committee meetings about ABP 501 and GP2015, the agency spent much of its time explaining and defending its approach to regulating biosimilars and bolstering the case for approval of Amgen's and Sandoz's products.

In addition to preclinical analytical comparisons and a 203-person PK similarity study, Amgen conducted two randomized, double-blind active comparator-controlled trials of ABP 501: a 526-patient rheumatoid arthritis (RA) trial and a 350-patient plaque psoriasis trial.

Richard Markus, VP of global biosimilars development at Amgen, told the committee the company "probably could have done one trial" but performed two "for additional comfort." As the first of a planned suite of Amgen biosimilars to reach FDA, the company clearly wasn't willing to take any avoidable risks with adalimumab.

However, FDA took the unusual step of admonishing Amgen for producing more clinical data than was required, and urging future biosimilars applicants to avoid unnecessary trials.

Nikolay Nikolov, clinical team leader in FDA's Division of Pulmonary, Allergy and Rheumatology Products, stressed the primacy of analytic data in establishing similarity. He noted the agency views clinical data as a tool to reduce "residual uncertainty" remaining after analytical characterization, not as a principal source of evidence of safety or efficacy.

It is "almost impossible" to design a clinical study that can detect differences between two very similar molecules, Nikolov said.

"There is no expectation that there will be studies in multiple indications," he added.

Nikolov said FDA "acknowledges the community's nervousness and need for reassurance that these products will work in different indications. Unfortunately, we are seeing biosimilar sponsors seeking to do multiple studies in multiple indications, which for us is not the right way to approach biosimilars."

For its etanercept, Sandoz supplemented its analytic characterization with PK studies and a switching study in which 531 plaque psoriasis patients were randomized to receive either GP2015 or Enbrel for 12 weeks, and then were switched between the two treatments at six-week intervals through week 30.

Rachel Glaser, an FDA medical officer, told the advisory committee that switching is not a requirement for approval and FDA has...

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